AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML

Ece Canan Sayitoglu; Bogdan A Luca; Allison Paige Boss; Benjamin Craig Thomas; Robert Arthur Freeborn; Molly Javier Uyeda; Pauline Ping Chen; Yusuke Nakauchi; Colin Waichler; Norman Lacayo; Rosa Bacchetta; Ravindra Majeti; Andrew J Gentles; Alma-Martina Cepika; Maria Grazia Roncarolo

doi:10.1038/s41375-024-02255-1

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML

Leukemia. 2024 May 9. doi: 10.1038/s41375-024-02255-1. Online ahead of print.

Authors

Ece Canan Sayitoglu^#¹, Bogdan A Luca^#², Allison Paige Boss¹, Benjamin Craig Thomas¹, Robert Arthur Freeborn¹, Molly Javier Uyeda^{1

3}, Pauline Ping Chen¹, Yusuke Nakauchi⁴, Colin Waichler¹, Norman Lacayo¹, Rosa Bacchetta^{1

5}, Ravindra Majeti^{3

4

6}, Andrew J Gentles², Alma-Martina Cepika⁷, Maria Grazia Roncarolo^{8

9

10}

Affiliations

¹ Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁴ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁵ Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁶ Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁷ Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA. acepika@stanford.edu.
⁸ Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA. mg1@stanford.edu.
⁹ Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. mg1@stanford.edu.
¹⁰ Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. mg1@stanford.edu.

^# Contributed equally.

PMID: 38724673
DOI: 10.1038/s41375-024-02255-1

Abstract

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4⁺ T cells. Single-cell RNA-seq of primary AML samples and CD4⁺ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4⁺ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8⁺ T cells in vitro, and engineered CD4⁺ T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.